Docosahexaenoic acid reduces microglia phagocytic activity via miR-124 and induces neuroprotection in rodent models of spinal cord contusion injury.

Microglia are activated after spinal cord injury (SCI), but their phagocytic mechanisms and link to neuroprotection remain incompletely characterized. Docosahexaenoic acid (DHA) has been shown to have significant neuroprotective effects after hemisection and compression SCI and can directly affect microglia in these injury models. In rodent contusion SCI, we demonstrate that DHA (500 nmol/kg) administered acutely post-injury confers neuroprotection and enhances locomotor recovery, and also exerts a complex modulation of the microglial response to injury. In rodents, at 7 days after SCI, the level of phagocytosed myelin within Iba1-positive or P2Y12-positive cells was significantly lower after DHA treatment, and this occurred in parallel with an increase in intracellular miR-124 expression. Furthermore, intraspinal administration of a miR-124 inhibitor significantly reduced the DHA-induced decrease in myelin phagocytosis in mice at 7 days post-SCI. In rat spinal primary microglia cultures, DHA reduced the phagocytic response to myelin, which was associated with an increase in miR-124, but not miR-155. A similar response was observed in a microglia cell line (BV2) treated with DHA, and the effect was blocked by a miR-124 inhibitor. Furthermore, the phagocytic response of BV2 cells to stressed neurones was also reduced in the presence of DHA. In peripheral monocyte-derived macrophages, the expression of the M1, but not the M0 or M2 phenotype, was reduced by DHA, but the phagocytic activation was not altered. These findings show that DHA induces neuroprotection in contusion injury. Furthermore, the improved outcome is via a miR-124-dependent reduction in the phagocytic response of microglia.

A Single Bolus of Docosahexaenoic Acid Promotes Neuroplastic Changes in the Innervation of Spinal Cord Interneurons and Motor Neurons and Improves Functional Recovery after Spinal Cord Injury.

Docosahexaenoic acid (DHA) is an ω-3 polyunsaturated fatty acid that is essential in brain development and has structural and signaling roles. Acute DHA administration is neuroprotective and promotes functional recovery in animal models of adult spinal cord injury (SCI). However, the mechanisms underlying this recovery have not been fully characterized. Here we investigated the effects of an acute intravenous bolus of DHA delivered after SCI and characterized DHA-induced neuroplasticity within the adult injured spinal cord. We found robust sprouting of uninjured corticospinal and serotonergic fibers in a rat cervical hemisection SCI model. A mouse pyramidotomy model was used to confirm that this robust sprouting was not species or injury model specific. Furthermore, we demonstrated that corticospinal fibers sprouting to the denervated side of the cord following pyramidotomy contact V2a interneurons. We also demonstrated increased serotonin fibers and synaptophysin in direct contact with motor neurons. DHA also increased synaptophysin in rat cortical cell cultures. A reduction in phosphatase and tensin homolog (PTEN) has been shown to be involved in axonal regeneration and synaptic plasticity. We showed that DHA significantly upregulates miR-21 and downregulates PTEN in corticospinal neurons. Downregulation of PTEN and upregulation of phosphorylated AKT by DHA were also seen in primary cortical neuron cultures and were accompanied by increased neurite outgrowth. In summary, acute DHA induces anatomical and synaptic plasticity in adult injured spinal cord. This study shows that DHA has therapeutic potential in cervical SCI and provides evidence that DHA could exert its beneficial effects in SCI via enhancement of neuroplasticity. SIGNIFICANCE STATEMENT: In this study, we show that an acute intravenous injection of docosahexaenoic acid (DHA) 30 min after spinal cord injury induces neuroplasticity. We found robust sprouting of uninjured corticospinal and serotonergic fibers in a rat hemisection spinal cord injury model. A mouse pyramidotomy model was used to confirm that the robust sprouting involved V2a interneurons. We show that DHA significantly upregulates miR-21 and phosphorylated AKT, and downregulates phosphatase and tensin homolog (PTEN), which is involved in suppressing anatomical plasticity, in corticospinal neurons and in primary cortical neuron cultures. We conclude that acute DHA can induce anatomical and synaptic plasticity. This provides direct evidence that DHA could exert its beneficial effects in spinal cord injury via neuroplasticity enhancement.

Laminin promotes vascular network formation in 3D in vitro collagen scaffolds by regulating VEGF uptake.

Angiogenesis is an essential neovascularisation process, which if recapitulated in 3D in vitro, will provide better understanding of endothelial cell (EC) behaviour. Various cell types and growth factors are involved, with vascular endothelial growth factor (VEGF) and its receptors VEGFR1 and VEGFR2 key components. We were able to control the aggregation pattern of ECs in 3D collagen hydrogels, by varying the matrix composition and/or having a source of cells signalling angiogenic proteins. These aggregation patterns reflect the different developmental pathways that ECs take to form different sized tubular structures. Cultures with added laminin and thus increased expression of α6 integrin showed a significant increase (p<0.05) in VEGFR2 positive ECs and increased VEGF uptake. This resulted in the end-to-end network aggregation of ECs. In cultures without laminin and therefore low α6 integrin expression, VEGFR2 levels and VEGF uptake were significantly lower (p<0.05). These ECs formed contiguous sheets, analogous to the 'wrapping' pathway in development. We have identified a key linkage between integrin expression on ECs and their uptake of VEGF, regulated by VEGFR2, resulting in different aggregation patterns in 3D.

Docosahexaenoic acid attenuates the early inflammatory response following spinal cord injury in mice: in-vivo and in-vitro studies.

BACKGROUND: Two families of polyunsaturated fatty acid (PUFA), omega-3 (ω-3) and omega-6 (ω-6), are required for physiological functions. The long chain ω-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have significant biological effects. In particular, DHA is a major component of cell membranes in the brain. It is also involved in neurotransmission. Spinal cord injury (SCI) is a highly devastating pathology that can lead to catastrophic dysfunction, with a significant reduction in the quality of life. Previous studies have shown that EPA and DHA can exert neuroprotective effects in SCI in mice and rats. The aim of this study was to analyze the mechanism of action of ω-3 PUFAs, such as DHA, in a mouse model of SCI, with a focus on the early pathophysiological processes. METHODS: In this study, SCI was induced in mice by the application of an aneurysm clip onto the dura mater via a four-level T5 to T8 laminectomy. Thirty minutes after compression, animals received a tail vein injection of DHA at a dose of 250 nmol/kg. All animals were killed at 24 h after SCI, to evaluate various parameters implicated in the spread of the injury. RESULTS: Our results in this in-vivo study clearly demonstrate that DHA treatment reduces key factors associated with spinal cord trauma. Treatment with DHA significantly reduced: (1) the degree of spinal cord inflammation and tissue injury, (2) pro-inflammatory cytokine expression (TNF-α), (3) nitrotyrosine formation, (4) glial fibrillary acidic protein (GFAP) expression, and (5) apoptosis (Fas-L, Bax, and Bcl-2 expression). Moreover, DHA significantly improved the recovery of limb function.Furthermore, in this study we evaluated the effect of oxidative stress on dorsal root ganglion (DRG) cells using a well-characterized in-vitro model. Treatment with DHA ameliorated the effects of oxidative stress on neurite length and branching. CONCLUSIONS: Our results, in vivo and in vitro, clearly demonstrate that DHA treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma.

Lentiviral mediated expression of a NGF-soluble Nogo receptor 1 fusion protein promotes axonal regeneration.

Nogo receptor 1 (NgR1) mediates the inhibitory effects of several myelin-associated inhibitors (MAIs) on axonal regeneration in the central nervous system. A truncated soluble NgR1 (sNgR) has been reported to act as a decoy receptor to block the actions of MAIs. In this study, we fused the sNgR to nerve growth factor (NGF) and used NGF as a carrier to deliver sNgR to the intercellular space to neutralize MAIs. NGF in NGF-sNgR remained biologically active and induced sprouting of calcitonin gene related peptide containing axons when expressed in the spinal cord using a lentiviral vector (LV). Secreted NGF-sNgR promoted neurite outgrowth of dissociated dorsal root ganglion neurons on myelin protein substrate. In a rat dorsal column transection model, regenerating sensory axons were found to grow into the lesion cavity in animals injected with LV/NGF-sNgR, while in animals injected with LV/GFP or LV/NGF-GFP few sensory axons entered the lesion cavity. The results indicate that NGF-sNgR fusion protein can reduce the inhibition of MAIs and facilitate sensory axon regeneration. The fusion constructs may be modified to target other molecules to promote axonal regeneration and the concept may also be adapted to develop gene therapy strategies to treat other disorders.

Activation of neuronal transient receptor potential vanilloid 1 channel underlies 20-hydroxyeicosatetraenoic acid-induced vasoactivity: role for protein kinase A.

A rise in intraluminal pressure triggers vasoconstriction in resistance arteries, which is associated with local generation of the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). Importantly, dysregulation of 20-HETE synthesis and activity has been implicated in several cardiovascular disease states, including ischemic disease, hypertension, and stroke; however, the exact molecular pathways involved in mediating 20-HETE bioactivity are uncertain. We investigated whether 20-HETE activates the transient receptor potential vanilloid 1 (TRPV1) and thereby regulates vascular function and blood pressure. We demonstrate that 20-HETE causes dose-dependent increases in blood pressure, coronary perfusion pressure (isolated Langendorff), and pressure-induced constriction of resistance arteries (perfusion myography) that is substantially attenuated in TRPV1 knockout mice and by treatment with the neurokinin 1 receptor antagonist RP67580. Furthermore, we show that both channel activation (via patch-clamping of dorsal root ganglion neurons) and vessel constriction are enhanced under inflammatory conditions, and our findings indicate a predominant role for protein kinase A-mediated sensitization of TRPV1 in these phenomena. Finally, we identify a prominence of these pathway in males compared with females, an effect we relate to reduced protein kinase A-induced phosphorylation of TRPV1. 20-HETE-induced activation of TRPV1, in part, mediates pressure-induced myogenic constriction and underlies 20-HETE-induced elevations in blood pressure and coronary resistance. Our findings identify a novel vasoconstrictor 20-HETE/TRPV1 pathway that may offer potential for therapeutic targeting in cardiovascular diseases associated with elevated 20-HETE implicated in dysregulated organ blood flow, such as stroke or hypertension.

Improved outcome after spinal cord compression injury in mice treated with docosahexaenoic acid.

In this study we have characterised the locomotor recovery, and temporal profile of cell loss, in a novel thoracic compression spinal cord injury (SCI) in the mouse. We have also shown that treatment with docosahexaenoic acid (DHA) is neuroprotective in this model of SCI, strengthening the growing literature demonstrating that omega-3 polyunsaturated fatty acids are neuroprotective after SCI. Compression SCI in C57BL/6 mice was produced by placing a 10 g weight for 5 min onto a 2 mm × 1.5 mm platform applied to the dura at vertebral level T12. Mice partly recovered from complete hindlimb paralysis and by 28 days post-surgery had plateaued at an average BMS locomotor score of 4.2, equivalent to weight support with plantar stepping. During the same period, neuronal loss at the epicentre increased from 26% of ventral horn neurons by day 1, to 68% by day 28. Delayed loss of oligodendrocytes was also seen (e.g. 84% by day 28 in the dorsal columns) and microglia/macrophage activation was maximal at 7 days. In contrast, axonal damage, judged by a decrease in the non-phosphorylated form of 200 kD neurofilament, was an early event, as the loss was seen by day 1 and did not change markedly over time. Mice that received an intravenous (i.v.) injection of 500 nmol/kg DHA 30 min after SCI, showed improved locomotor recovery and, at 28 day survival, reduced neuronal, oligodendrocyte and neurofilament loss, and reduced microglia/macrophage activation. For some of these indices of SCI, enrichment of the diet with 400 mg/kg/day DHA led to further improvement. However, dietary DHA supplementation, without the initial i.v. injection, was ineffective.

The spatiotemporal localization of JAM-C following sciatic nerve crush in adult rats.

JAM-C is a junctional adhesion molecule, enriched at tight junctions on endothelial and epithelial cells, and also localized to Schwann cells at junctions between adjoining myelin end loops. The role of JAM-C following peripheral nerve injury (PNI) is currently unknown. We examined the localization of JAM-C after sciatic nerve crush injury in adult rats. JAM-C immunoreactivity was present in paranodes and incisures in sham surgery control nerve, but distal to the crush injury significantly decreased at three and 14 days. JAM-C was re-expressed at 28 days and, by 56 days, was significantly increased in the distal nerve compared to controls. In a 7-mm length of sciatic nerve sampled distal to the crush site, the densities of JAM-C immunoreactive paranodes increased in the distal direction. Conversely, the densities of JAM-C immunoreactive incisures were highest immediately distal to the crush site and decreased in the more distal direction. Further analysis revealed a strong correlation between JAM-C localization and remyelination. Fifty-six days after crush injury, greater densities of JAM-C paranodes were seen compared to the nodal marker jacalin, suggesting that paranodal JAM-C precedes node formation. Our data are the first to demonstrate a potential role of JAM-C in remyelination after PNI.

Docosahexaenoic acid, but not eicosapentaenoic acid, reduces the early inflammatory response following compression spinal cord injury in the rat.

Docosahexaenoic acid (DHA, 22 : 6) and eicosapentaenoic acid (EPA, 20 : 5) are omega-3 polyunsaturated fatty acids (n-3 PUFAs) with distinct anti-inflammatory properties. Both have neuroprotective effects acutely following spinal cord injury (SCI). We examined the effect of intravenous DHA and EPA on early inflammatory events after SCI. Saline, DHA or EPA (both 250 nmol/kg) were administered 30 min after T12 compression SCI, to female Sprague-Dawley rats. DHA significantly reduced the number of neutrophils to some areas of the injured epicentre at 4 h and 24 h. DHA also reduced C-reactive protein plasma levels, whereas EPA did not significantly reduce neutrophils or C-reactive protein. Laminectomy and SCI elicited a sustained inflammatory response in the liver, which was not reversed by the PUFAs. The chemokine KC/GRO/CINC and the cytokine IL-6 provide gradients for chemotaxis of neutrophils to the epicentre. At 4 h after injury, there was a significant increase in IL-6, KC/GRO/CINC, IL-1ß and tumour necrosis factor-α in the epicentre, with a return to baseline at 24 h. Neither DHA nor EPA returned their levels to control values. These results indicate that the acute neuroprotective effects of n-3 PUFAs in rat compression SCI may be only partly attributed to reduction of some of the early inflammatory events occurring after injury.

Schwann cell-specific JAM-C-deficient mice reveal novel expression and functions for JAM-C in peripheral nerves.

Junctional adhesion molecule-C (JAM-C) is an adhesion molecule expressed at junctions between adjacent endothelial and epithelial cells and implicated in multiple inflammatory and vascular responses. In addition, we recently reported on the expression of JAM-C in Schwann cells (SCs) and its importance for the integrity and function of peripheral nerves. To investigate the role of JAM-C in neuronal functions further, mice with a specific deletion of JAM-C in SCs (JAM-C SC KO) were generated. Compared to wild-type (WT) controls, JAM-C SC KO mice showed electrophysiological defects, muscular weakness, and hypersensitivity to mechanical stimuli. In addressing the underlying cause of these defects, nerves from JAM-C SC KO mice were found to have morphological defects in the paranodal region, exhibiting increased nodal length as compared to WTs. The study also reports on previously undetected expressions of JAM-C, namely on perineural cells, and in line with nociception defects of the JAM-C SC KO animals, on finely myelinated sensory nerve fibers. Collectively, the generation and characterization of JAM-C SC KO mice has provided unequivocal evidence for the involvement of SC JAM-C in the fine organization of peripheral nerves and in modulating multiple neuronal responses.

Arachidonyl trifluoromethyl ketone is neuroprotective after spinal cord injury.

In spinal cord injury (SCI), neuronal and oligodendroglial loss occurs as a result of the initial trauma and the secondary damage that is triggered by excitotoxicity, free radicals, and inflammation. There is evidence that SCI ellicits increased cytosolic phospholipase A(2) (cPLA(2)) activity. The cleavage of phospholipids by cPLA(2) leads to release of fatty acids, and in particular arachidonic acid (AA), the metabolites of which have been associated with increased inflammation and oxidative stress. The aim of our study was to investigate whether the inhibition of cPLA(2) following SCI leads to tissue protection and an improved functional outcome. Adult rats received compression SCI and 30 min after injury they were treated intravenously with either saline or the cPLA(2) inhibitor arachidonyl trifluoromethyl ketone (AACOCF3) (7.13 mg/kg). The animals were sacrificed at 7 days post-injury and the lesioned tissue was labeled using markers for neurons, oligodendrocytes, and macrophages/activated microglia. We also assessed locomotor recovery using the Basso-Beattie-Bresnahan (BBB) score. The number of surviving neurons and oligodendrocytes was significantly increased in animals treated with the cPLA(2) inhibitor compared to saline controls. The behavioral analysis mirrored the neuroprotective effects and showed that the inhibitor-treated group had better locomotor recovery compared to saline controls. Our results show that AACOCF3 has neuroprotective potential, and support the idea that cPLA(2) is critically involved in acute spinal injury.

TRPC4 in rat dorsal root ganglion neurons is increased after nerve injury and is necessary for neurite outgrowth.

Canonical transient receptor potential (TRPC) receptors are Ca(2+)-permeable cation channels that have a variety of physiological functions and may be involved in neuronal development and plasticity. We investigated the expression profile of TRPC channels in adult rat dorsal root ganglia (DRG) after nerve injury and examined the role of TRPC4 in neurite outgrowth in cultured DRG neurons. Sciatic nerve transection and microinjection of dibutyryl cAMP were employed to induce axonal regeneration in vivo. TRPC4 mRNA was significantly increased whereas TRPC1, TRPC3, TRPC6, and TRPC7 remained unaltered after nerve injury or dibutyryl-cAMP microinjection. The increases in TRPC4 transcript and protein were transient with maximal levels reached at 2 or 7 days, respectively. In addition, TRPC4 transcript in ND7/23 and NDC cells, hybrid cell lines derived from neonatal DRG and neuroblastoma, was substantially increased on differentiation, characterized by neurite outgrowth. In adult DRG, TRPC4 immunoreactivity was found in small and large neurons, and nerve injury increased the number of TRPC4-immunoreactive cells, particularly in large neurons. TRPC4 immunoreactivity was present in growth cones at various stages of DRG neurite outgrowth in vitro. Suppression of TRPC4 by a specific small interfering RNA or antisense significantly reduced the length of neurites in cultured DRG neurons. Expression of short hairpin RNA significantly down-regulated TRPC4 protein level and shortened neurite lengths in differentiated ND7/23 cells. The reduction in neurite lengths in ND7/23 cells was rescued by overexpression of human TRPC4. Our results suggest that TRPC4 contributes to axonal regeneration after nerve injury.

TRPV1, but not P2X, requires cholesterol for its function and membrane expression in rat nociceptors.

We examined the importance of membrane cholesterol for the function and expression of TRPV1 (vanilloid receptor subtype 1) and P2X(3) in adult rat dorsal root ganglion (DRG) neurons. Cholesterol, an essential component of lipid rafts, was depleted using methyl beta-cyclodextrin (MCD). We found that MCD significantly reduced TRPV1-mediated capsaicin- and proton-activated currents. By contrast, inward currents activated by alpha,beta-methylene ATP (alpha,beta-meATP), a non-hydrolysable ATP analogue, were not altered. Immunoreactivity for TRPV1, but not P2X(3), in the plasma membrane was markedly reduced by MCD. A reduction of TRPV1 protein in membrane fractions was found following cholesterol depletion. Our data show that the level of cholesterol determines the activity and the amount of membrane TRPV1, suggesting that TRPV1 might be localized in cholesterol-rich microdomains in nociceptors. The differential dependence on the membrane cholesterol of TRPV1 and P2X(3) may have physiological significance in nociception during inflammation.

ATF3 expression in L4 dorsal root ganglion neurons after L5 spinal nerve transection.

Activating transcription factor 3 (ATF3) is a widely used marker of damaged primary sensory neurons that is induced in essentially all dorsal root ganglion (DRG) neurons by spinal nerve axotomy. Whether such injuries induce its expression in neurons of adjacent DRGs remains unknown. Following L5 spinal nerve ligation, experimental but not sham-operated rats develop thermal and mechanical hypersensitivity. In the L4 DRG, 11-12% of neurons were ATF3 positive by 1 day post-surgery, and numbers remain unchanged at 2 weeks. Importantly, sham exposure of the L5 spinal nerve produced a nearly identical number of ATF3-positive neurons in the L4 DRG and also a substantial increase in the L5 DRG, with a similar time-course to experimental animals. There was no correlation between behaviour and magnitude of ATF3 expression. Co-localization studies with the DRG injury markers galanin, neuropeptide Y and nitric oxide synthase (NOS) showed that approximately 75, 50 and 25%, respectively, of L4 ATF3-positive neurons co-expressed these markers after L5 transection or sham surgery. Additionally, increases in galanin and NOS were seen in ATF3-negative neurons in L4. Our results strongly suggest that the surgical exposure of spinal nerves induces ATF3 in the L4-5 DRG, irrespective of whether the L5 nerve is subsequently cut. This probably reflects minor damage to the neurons or their axons but nevertheless is sufficient to induce phenotypic plasticity. Caution is therefore warranted when interpreting the phenotypic plasticity of DRG neurons in adjacent ganglia in the absence of positive evidence that they are not damaged.

Degeneration of primary afferent terminals following brachial plexus extensive avulsion injury in rats / Degeneración de los terminales aferentes primarios de rata luego de lesión extensa por avulsión del plexo braquial

Important breakthroughs in the understanding regeneration failure in an injured CNS have been made by studies of primary afferent neurons. Dorsal rhizotomy has provided an experimental model of brachial plexus (BP) avulsion. This is an injury in which the central branches of primary afferents are disrupted at their point of entry into the spinal cord, bringing motor and sensory dysfunction to the upper limbs. In the present work, the central axonal organization of primary afferents was examined in control (without lesion) adult Wistar rats and in rats subjected to a C3-T3 rhizotomy. Specific sensory axon subtypes were recognized by application of antibodies to the calcitonin gene-related peptide (CGRP), the P2X3 purinoreceptor, the low-affinity p75-neurotrophin receptor and the retrograde tracer cholera toxin subunit beta (TCbeta ). Other subtypes weres labeled with the lectin Griffonia simplicifolia IB4. Using immunohistochemistry and high resolution light microscopy, brachial plexus rhizotomy in adult rats has proven a reliable model for several neural deficits in humans. This lesion produced different degrees of terminal degeneration in the several types of primary afferents which define sub-populations of sensitive neurons. Between the C6 and C8 levels of the spinal cord,,deafferentation was partial for peptidergic GCRP-positive fibers, in contrast with elimination of non peptidergic and myelinated fibers. Dorsal rhizotomy has provided an adequate experimental model to study sensory alterations such as acute pain and allodynia as well as factors that affect regeneration into the CNS., Therefore, the differential deafferentation response must be considered inr the evaluation of therapies for nociception (pain) and regeneration for brachial plexus avulsion. The anatomical diffierences among the primary afferent subtypes also affect their roles in normal and damaged conditions.

El uso de las neuronas sensoriales primarias ha aportado avances en el entendimiento de las razones por las cuales falla la regeneración cuando el sistema nervioso central (SNC) es dañado. La rizotomía dorsal se puede usar como un modelo experimental de las lesiones por avulsión del plexo braquial, una lesión en la cual son desprendidas, en su punto de entrada en la médula espinal, las ramas centrales de los aferentes primarios causando una disfunción motora y sensorial grave e irreversible del miembro superior. En el presente trabajo, se examinó la organización central de los aferentes primarios en ratas Wistar adultas. Éstas fueron divididas en controles normales no lesionados y en animales rizotomizados entre los niveles cervical 3 y torácico 3 (C3-T3). Se estudió la deaferentación de los subtipos de axones sensoriales utilizando anticuerpos específicos contra el péptido relacionado con el gen de la calcitonina (CGRP), el receptor purinérgico (P2X3), el receptor de baja afinidad p75 para el factor de crecimiento nervioso (NGF) y contra la subunidad ®de la toxina de cólera (TCbeta ). Otro subtipo fue marcado con la lectina Griffonia simplicifolia IB4. La inmunohistoquímica y la microscopía óptica de alta resolución demostraron que el modelo animal de rizotomía completa del plexo braquial reproduce diversos déficit observados en las lesiones humanas. Esta lesión produce diferentes grados de degeneración terminal entre los diversos tipos de aferentes primarios que definen subpoblaciones de neuronas sensoriales. En los niveles de la médula espinal estudiados (entre C6 y C8), la deaferentación fue parcial para las fibras peptidérgicas GCRPpositivas, en contraste con la eliminación de las fibras no peptidérgicas y las mielinizadas. La rizotomía dorsal es un modelo experimental apropiado para estudiar las alteraciones sensoriales como el dolor agudo y la alodinia, así como los factores que podrían afectar la regeneración en el SNC. Por tanto, la respuesta de deaferentacion diferencial debe ser tenida en cuenta para la evaluación de terapias antinociceptivas y regenerativas tras la avulsión del plexo braquial. Se discute la anatomía de los subtipos de aferentes primarios y su papel en condiciones normales y después de la lesión.

Mutations in dynein link motor neuron degeneration to defects in retrograde transport.

Degenerative disorders of motor neurons include a range of progressive fatal diseases such as amyotrophic lateral sclerosis (ALS), spinal-bulbar muscular atrophy (SBMA), and spinal muscular atrophy (SMA). Although the causative genetic alterations are known for some cases, the molecular basis of many SMA and SBMA-like syndromes and most ALS cases is unknown. Here we show that missense point mutations in the cytoplasmic dynein heavy chain result in progressive motor neuron degeneration in heterozygous mice, and in homozygotes this is accompanied by the formation of Lewy-like inclusion bodies, thus resembling key features of human pathology. These mutations exclusively perturb neuron-specific functions of dynein.